RU2562017C2 - Fabrication of filled container for inhaler - Google Patents

Abstract

FIELD: process engineering.

SUBSTANCE: in compliance with this process, air-filled container case hole is sealed and connected to filling device. Fluid and/or gas from filling device is forced into container. Note here that fluid and/or gas includes at least propellant. Note also that prior to filling the container with gas or fluid it is free of propellant while after its filling it is, in fact, filled with propellant first portion and air second portion. Filled container for inhaler is produced as described above. Dispensing inhaler, preferably inhaler activate by breath includes above described filled container.

EFFECT: higher reliability.

18 cl, 7 dwg, 3 tbl, 3 ex

Description

The present invention relates to a method for producing a filled container for an inhaler, in particular, a method for providing a container suitable for use in a metered dose inhaler and filling the container with drug components.

Inhalers, such as dry powder inhalers (DPI) and metered-dose metered-dose inhalers (pMDI), are often used to deliver a wide variety of drugs. pMDI includes at least one drug container, activated, for example, by opening the metering valve, with the delivery of a dose of the drug to the user through the mouthpiece. The inhaler may be manually actuated and / or may be provided with a drive mechanism for automatically actuating the container, for example, a breath activated mechanism that operates in response to inhalation of the user. Such inhalation activated inhalers (BA1) ensure that the dose of the drug released when the container is actuated is delivered during the inhalation of the user, which is especially useful for users who may find it difficult to coordinate the release of the drug with the inhalation of this dose.

A typical drug for pMDI contains at least one active pharmaceutical ingredient (API) and preferably at least one of: a propellant (preferably one of several ozone-saving propellants approved for inhalation use, such as 1,1,1,2-tetrafluoroethane ( HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227)) and any other suitable components such as surfactant (s), cosolvent (s), lubricating ( ii) substance (a) and so on. The drug may be a suspension or solution, or a mixture thereof.

A drug container suitable for use in pMDI can be prepared in one of a number of conventional ways. Typically, for filling with a suitable drug, the containers are fed to a filling line or a filling step is carried out. In conventional systems, the container may be subjected to one or more than one suitable preparatory stage before the filling step, such as cleaning by blowing with compressed air and / or by suction under vacuum and blowing with a propellant, and so on. The container is then filled with a suitable and precisely defined amount of the drug, which is usually dispensed into the container by weight or volume. Instead, or in addition, the container can be weighed after filling to confirm the presence of a precisely defined amount of the drug in the container.

Several methods are known for filling a pMDI container with a drug in the form of a solution or suspension, including cold filling and pressurized filling (usually one-step or two-step). In the cold filling method, the volatile propellant is cooled to a temperature below its boiling point, which leads to its liquefaction. One or more APIs, as well as any other components of the drug, are usually mixed with this liquefied propellant, and this drug is fed into a filling nozzle from which it is dispensed into a container on the filling line. The container is then sealed, usually with any suitable metering valve. The disadvantage of this method is the need for precise control and maintenance of low temperatures at all stages of the system (especially in the mixing tank and the tubes from it to the nozzle and so on). Such low temperature systems are expensive, difficult to use, and lead to problems associated with condensation of water vapor in the drug. In addition, any changes in temperature can affect the concentration of the dose provided by the container during use, which causes serious harm to the drug.

An alternative way to add the drug to the container is to fill under pressure. This method is preferable to cold filling because it does not require cooling of the system components to temperatures low enough to liquefy the propellant.

For a long time it was believed that both the pressure filling method and the cold filling method require a purge step, as discussed above, firstly, to ensure that the pressure in the filled container is not too high (since it was believed that this could cause the container to rupture during or after filling), and also to ensure that oxygen is substantially removed from the container to prevent any chemical decomposition of the product due to oxidation, and additionally to ensure So that moisture was substantially removed from the container.

A significant advantage of cold filling the container is that the volatile liquid itself removes air from the container (since a certain amount of propellant will inevitably evaporate and displace air from the container before closing the valve), while the pressure filling method usually does not provide such deaeration by itself (with the exception of the two-stage method, in which the concentrate contains a volatile component heavier than air).

Therefore, the standard method of filling under pressure (one-stage or two-stage) includes purging as the first stage of the method, immediately before filling the container. The purge step usually involves the introduction of a few drops of a liquefied propellant into an empty container, which evaporates quickly (upon contact with a warm container) and forces air to be displaced from the container, immediately after which the container is ready to be filled under pressure, as described above. This is a disadvantage, since the introduction of any additional stage requires time, increases the cost and, in addition, leads to the inevitable release of excess propellant into the environment.

In the method of filling under pressure, the propellant is liquefied under pressure. In the conventional two-stage method of filling under pressure, one or more APIs and, as a rule, any other components of the drug (e.g., cosolvent (s), surfactant (s), non-volatile liquid (s) and so on further) pre-mixed to obtain a concentrate, which is filled in an empty container. If necessary, the concentrate can be cooled. The container is then sealed with a metering valve and a liquefied propellant is introduced into the sealed container through this valve, mixing it with the concentrate to produce the desired drug. A typical one-stage method of filling under pressure is similar to the two-stage method, except that the concentrate is also pre-mixed with propellant under pressure and the resulting mixture is introduced into a sealed container through a metering valve.

More detailed known container filling methods are described in the art, for example, in Metered Dose Inhaler Technology pp. 79-107 (Tol S. Purewal & David J. W. Grant, eds., 1998).

According to the present invention, a method for producing a filled container containing a medicament for an inhaler is provided, which overcomes the disadvantages of the prior art. This is achieved by the method as defined in the independent claims.

In a first broad aspect, a method for producing a filled container for an inhaler is provided, comprising the steps of:

providing a container with a housing configured to contain the drug and with an opening for loading the drug, said container being substantially filled with air under ambient conditions;

sealing said opening of an air-filled container by installing a metering valve or other sealing means therein;

attaching said sealed air-filled container to a filling device; and

distributing pressurized liquids and / or gas from said filling device to said pressurized container filled with air through said dispensing valve or other sealing means, said pressurized liquid and / or gas containing at least a propellant,

wherein:

prior to said step of dispensing pressurized liquids and / or gas, the sealed container is substantially free of propellant; and

after this stage of the distribution of pressurized liquid and / or gas, the sealed container is essentially filled with at least a first part of the propellant and a second part of air.

The present invention also includes a container filled with at least some components of the drug by the method of the present invention, and an inhaler containing a container filled with components of the drug by the method of the present invention.

Embodiments of the present invention are defined in the dependent claims.

The advantage provided by the present invention is that the significant cooling processes required in the cold filling method are not required, and in addition, the purging step necessary in the pressure filling method and the associated disadvantages are avoided. In addition, a problem associated with conventional pMDI devices is that there may be a reduction in the released mass of the aerosol subsequently atomized if the metering valve of the device is kept in the actuated or open position for a long period of time after the previous actuation. It was unexpectedly found that this effect is significantly weakened if the container is filled with the drug without first purging it. Thus, according to embodiments of the present invention, the container is not purged, unlike conventional methods. On the contrary, the container is left filled with ambient gas, that is, air, and sealed with a metering valve (hermetically in the closed position of the valve), while the container is still filled with air. Specifically, at no stage before the container is sealed is it intentionally injected into it (to remove air) a certain or substantial amount of propellant or other liquid or gas for purging, and the container is filled with propellant (or propellant mixed with drug components) when the container still contains air. Such a container, not subjected to a deliberate purge process (to remove or displace air) before sealing and filling, is called a container that has not been purged. In some embodiments, an active pharmaceutical ingredient (API) and / or other drug components may be added prior to sealing the container with a metering valve, but for the avoidance of doubt this does not include any purge propellant since the container is not purged.

The inventors unexpectedly found that, contrary to the ideas of the prior art, the pressure in the container that has not been purged (that is, a container that has not been purged with a volatile propellant before filling with the drug, as in the traditional method of filling under pressure), does not exceed safe limits. In addition, it was unexpectedly discovered that the presence of oxygen is harmless to many products. Moreover, the inventors have found that the amount of water typically remaining in the container can be reduced by controlling the local environmental conditions around the filling device. Thus, the inventors unexpectedly found that for many products the purge step is not necessary. Eliminating the purge step provides the advantage of reducing the amount of propellant, such as HFA, released into the atmosphere during the filling process (to ensure full purge, it is standard practice to add a small excess of propellant to the container, and a small amount of propellant can be emitted from each container to the atmosphere) . In addition, eliminating the purge step increases the efficiency and reliability of the filling method by eliminating one of the process steps.

As described above, the inventors have provided an advantage by finding that non-purged containers are suitable for use in pMDI, in particular inhalation-activated inhalers, and that unwanted release of the propellant during the provision and filling of the container is thereby minimized. In addition, the unwanted reduction in the released mass that can occur during subsequent actuation when the metering valve remains open for a long period of time is minimized. This advantage is particularly important for devices in which the metering valve can be held open, such as hand-operated devices that the patient can hold in the actuated or open position, or devices, for example, with a release mechanism after actuation, or automatic control devices, such as a breath-activated inhaler, where the response force is restored, in some cases the patient does this manually after being actuated. Not wishing to be bound by theory, they argue that this advantage can be achieved due to the higher pressure in the containers that have not been purged compared to traditional containers subjected to purging, which leads to better filling of the chamber of the metering valve, even after holding the valve in action position for a long period of time.

The inventors have also proposed an alternative method for producing a container containing a drug for an inhaler, in particular a method for providing a container suitable for a metered-dose inhaler and filling the container with a drug (or its components). An alternative method also minimizes unwanted release of the propellant during the provision and filling of the container, but not by offering sealed containers substantially free of propellant (i.e., containers that have not been purged). More preferably, and according to another broad aspect of the present invention, a new method for purging and filling a container for use in an inhaler is provided, comprising the steps of:

providing a container with a housing configured to contain the drug and with an opening for loading the drug, said container being substantially filled with air;

dispensing a certain amount of a substance, which is any substance, with the exception of the propellant, and preferably being an inert substance, into a container so as to displace a significant portion of the air, thereby obtaining a container substantially filled with said substance;

sealing the openings of said container by installing a metering valve or other sealing means thereon, insulating said substance therein;

connecting said sealed container to a filling device; and

distributing pressurized liquids and / or gas from said filling device to said pressurized container through said dispensing valve or other sealing means,

wherein said pressurized liquid and / or gas contain at least a propellant,

with obtaining thus sealed container containing at least the first part of the propellant and the second part of the specified substance.

The substance may be any suitable substance, with the exception of the propellant. Preferably, the substance is any substance except for the HFA propellant or the CFC propellant, more preferably with the exception of HFA 227 or HFA 134a. Preferably, the substance comprises an inert substance, such as nitrogen or argon, or may include carbon dioxide. Preferably, the substance has a gaseous and / or liquid form. The substance may be under ambient pressure, or the substance may be under increased pressure. The substance may be at ambient temperature or may be chilled.

The container according to any of the above aspects may be any container suitable for storing a drug. Preferably, the container includes a material such as aluminum, glass or the like. Preferably, the container is coated, preferably the coating is applied to at least a portion of the inner surface, or more preferably to substantially the entire inner surface of the container. The coating may contain any substance or composition suitable for use in contact with the drug. In a preferred embodiment, the coating comprises a polymer or a mixture of polymers. Preferably, the coating comprises a fluorine-containing polymer. Preferably, the coating comprises perfluoroalkoxyethylene (PFA), polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), polyethylene terephthalate (PET) or the like. Coating may be applied by any suitable technique. Preferably, the container is coated by any suitable method, such as immersion, dry powder coating, spraying or, preferably, plasma spraying. The container may be preheated before coating, and / or it may be heated after coating by calcining or calcining the coating.

A medicine may contain various active ingredients. The active ingredient may be selected from any therapeutic or diagnostic agent. For example, the active ingredient may be an antiallergic agent, a bronchodilator (e.g., a beta-2 adrenergic receptor agonist, or a muscarinic receptor antagonist, or one compound having both of these properties), a bronchoconstrictor, pulmonary surfactant, an analgesic, an antibiotic, a mast cell inhibitor, an antihistamine agent, anti-inflammatory agent, antitumor agent, anesthetic, anti-tuberculosis agent, imaging agent, agent for the treatment of cardiovascular diseases, enzyme, steroid, gene synthetic material, viral vector, antisense agent, protein (such as insulin), peptide, non-steroidal glucocorticoid receptor agonist (GR receptor), antioxidant, chemokine antagonist (e.g. CCR1 antagonist), corticosteroid, CRTh2 antagonist, DP1 antagonist, gon inducer, IKK2 inhibitor, cyclooxygenase inhibitor (COX), lipoxygenase inhibitor, leukotriene receptor antagonist, myeloperoxidase inhibitor (MPO), p38 inhibitor, phosphodiesterase inhibitor (PDE), peroxisome proliferator-activated γ agonist (PPAR-γ), protease inhibitor, statin, trobmoxane antagonist, vasodilator, ENAC blocker (sodium channel epithelial blocker), and combinations thereof.

Examples of specific active ingredients that may be included in a drug include:

1) antioxidants: allopurinol, erdostein, mannitol, N-acetylcysteine choline ether, M-acetylcysteine ethyl ester, N-acetylcysteine, N-acetylcysteinamide and nicotinic acid;

2) chemokine antagonists: BX471 (monohydrochloride (2R) -1 - [[2 - [(aminocarbonyl) amino] -4-chlorophenoxy] acetyl] -4 - [(4-fluorophenyl) methyl] -2-methylpiperazine), CCX634, N- {2 - [((2S) -3 - {[1 - (4-chlorobenzyl) piperidin-4-yl] amino} -2-hydroxy-2-methylpropyl) oxy] -4-hydroxyphenyl} acetamide (see WO 2003/051839) and 2- {2-chloro-5 - {[((2S) -3- (5-chloro-1'H, 3H-spiro [1-benzofuran-2,4e-piperidine] -1'- il) -2-hydroxypropyl] oxy} -4 - [(methylamino) carbonyl] phenoxy} -2-methylpropanoic acid (see WO 2008/010765), 656933 (N- (2-bromophenyl) -N '- (4- cyano-1H-1,2,3-benzotriazol-7-yl) -urea), 766994 (4 - ({[({[((2R) -4- (3,4-dichlorobenzyl) -morpholin-2-yl] methyl} amino) carbonyl] amino} methi k) benzamide), SSX-282, SSX-915, cyanovirin N, E-921, INCB-003284, INCB-9471, maraviroc, MLN-3701, MLN-3897, T-487 (N- {1- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydropyrido [2,3-d] pyrimidin-2-yl] ethyl} -N- (pyridin-3-ylmethyl) -2- [4- (trifluoromethoxy) phenyl ] acetamide) and vicriviroc;

3) corticosteroids: aclomethasone dipropionate, amelomethasone, beclomethasone dipropionate, budesonide, butyxocort propionate, cyclesonide, clobetasol propionate, desisobutyryl cyclesonide, ethiprednolonefononefonolonefonazone fluconazole, use of etiprednolonefonetonefononefononefononefonetone, use

4) DP1 antagonists: L888839 and MK0525;

5) histone deacetylase inducers: ADC4022, aminophylline, methylxanthine or theophylline;

6) IKK2 inhibitors: 2 - {[2- (2-methylaminopyrimidin-4-yl) -1H-indole-5-carbonyl] amino} -3- (phenylpyridin-2-ylamino) -propanoic acid;

7) cyclooxygenase (COX) inhibitors: celecoxib, sodium diclofenac, etodolac, ibuprofen, indomethacin, meloxicam, nimesulide, OS 1768, OS2125, OS2184, OS499, OCD9101, sodium parecoxib, piceatannol, piroxicib and rofecib;

8) lipoxygenase inhibitors: ajulemic acid (ajulemic acid), darbufelon, darbufelon mesylate, dexibuprofen-lysine (monohydrate), sodium etalocib, lycofelon, linazolast, lonapalen, mazoprokol, MN-001, teploxalon, UlV-35, UlopV-35, UlfV-35, UlofL-40, Velofilon, Ulon , ZD-4007 and zileuton ((±) -1- (1-benzo [b] thien-2-yl-ethyl) -1-hydroxyurea);

9) antagonists of leukotriene receptors: ablukast, ralukast (CGP 45715A), montelukast, montelukast sodium, ontazolast, pranlukast, pranlukast hydrate (monosodium salt), verlukast (MK-679) and zafirlukast;

10) MPO inhibitors: hydroxamic acid derivative (N- (4-chloro-2-methylphenyl) -4-phenyl-4 - [[(4-propan-2-ylphenyl) sulfonylamino] methyl] -piperidin-1-carboxamide), piceatannol and resveratrol;

11) beta-2-adrenoreceptor agonists: metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g., in the form of sulfate), formoterol (e.g., in the form of fumarate), salmeterol (e.g., in the form of xinafoate), terbutaline, orciprenolaline, e.g. in the form of mesylate), pirbuterol, indacaterol, salmeterol (e.g. in the form of xinafoate), bambuterol (e.g. in the form of the hydrochloride), carmoterol, indacaterol (CAS No. 312753-06-3; QAB-149), formanilide derivatives, eg 3- (4 - {[6 - ({(2R) -2- [3- (formylamino) -4-hydroxyphenyl] -2-hydroxyethyl} amino) hexyl] hydroxy} -butyl) -benzenesulfonamide; 3- (4 - {[6 - ({((2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -hexyl] oxy} butyl) benzene sulfonamide; GSK 159797, GSK 159802, GSK 597901, GSK 642444, GSK 678007; and a compound selected from N- [2- (diethylamino) ethyl] -N- (2 - {[2- (4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl) -ethyl] amino} -ethyl) ”3- [2- (1-naphthyl) ethoxy] propanamide, N- [2- (diethylamino) ethyl] -N- (2 - {[2- (4-hydroxy-2- oxo-2,3-dihydro-1,3-benzothiazol-7-yl) ethyl] amino} ethyl) -3- [2- (3-chlorophenyl) ethoxy] propanamide, 7 - [(1P) -2 - ({2 - [(3 - {[2- (2-chlorophenyl) ethyl] amino} propyl) thio] ethyl} amino) -1-hydroxyethyl] -4-hydroxy-1,3-benzothiazole-2 (3H ) -one and N-cyclohexyl-N ³ - [2- (3-fluorophenyl) ethyl] -N- (2 - {[2- (4-hydroxy-2-oxo-2,3-dihydro-1,3- benzothiazol-7-yl) ethyl] amino} ethyl) -β-alaninamide or a pharmaceutically acceptable salt thereof (e.g. ep, where the counterion is a hydrochloride (e.g., monohydrochloride or dihydrochloride), hydrobromide (e.g., monohydrobromide or dihydrobromide), fumarate, methanesulfonate, ethanesulfonate, benzenesulfonate, 2,5-dichlorobenzenesulfonate or 1,5-dichlorobenzenesulfonyl sulfonate sulfonate naphthalene-1- (sulfonic acid) -5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane-1- (sulfonic acid) -2-sulfonate), D-mandelate, L-mandelate, cinnamate or benzoate) ;

12) muscarinic receptor antagonists: aclidinium bromide, glycopyrrolate (such as R, R-, R, S-, S, R- or S, S-glycopyrronium bromide), oxytropium bromide, pirenzepine, telenzepine, tiotropium bromide, 3 bromide (R ) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane, bromide (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2- thien-2-yl-acetoxy] -1- (2-phenoxyethyl) -1-azoniabicyclo [2.2.2] octane, a quaternary salt (such as the salt of [2 - ((R) -cyclohexylhydroxyphenylmethyl) -oxazole-5-ylmethyl] dimethyl - (3-phenoxypropyl) -ammonium, salt of [2- (4-chlorobenzyloxy) ethyl] - [2 - ((R) -cyclohexylhydroxyphenylmethyl) - oxazol-5-ylmethyl] dimethylammonium and the salt of (R) -1- [2- (4-fluorophenyl) ethyl] -3 - ((S) -2-phenyl-2-piperidin-1-ylpropionyloxy) -1- azoniabicyclo [2.2.2] octane, where the counterion is, for example, chloride, bromide, sulfate, methanesulfonate, benzenesulfonate (besylate), toluene sulfonate (tosylate), naphthalene bissulfonate (atapisylate or heminapadisylate), phosphate, acetate, citrate, citrate, mesylate, maleate, fumarate or succinate);

13) p38 inhibitors: 681323, 856553, AMG548 (2 - [[(2S) -2-amino-3-phenylpropyl] amino] -3-methyl-5- (2-naphthalenyl) -6- (4-pyridinyl) - 4 (3H) -pyrimidinone), Array-797, AZD6703, doramapimod, KS-706, PH 797804, R1503, SC-80036, SCI0469, 6-chloro-5 - [[(2S, 5R) -4 - [(4 -fluorophenyl) methyl] -2,5-domethyl-1-piperazinyl] carbonyl] -N, N, 1-trimethyl-α-oxo-1H-indole-3-acetamide, VX702 and VX745 (5- (2.6- dichlorophenyl) -2- (phenylthio) -6H-pyrimido [1,6-b] pyridazin-6-one);

14) PDE inhibitors: 256066, arophylline (3- (4-chlorophenyl) -3,7-dihydro-1-propyl-1H-purin-2,6-dione), AWD 12-281 (N- (3,5- dichloro-4-pyridinyl) -1 - [(4-fluorophenyl) methyl] -5-hydroxy-a-oxo-1 H-indole-3-acetamide), BAY19-8004 (Bayer), CDC-801 (Calgene), compound Celgene ((βR) -β- (3,4-dimethoxyphenyl) -1.3-dihydro-1-oxo-2H-isoindole-2-propanamide), cilomilast (cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexanecarboxylic acid), 2- (3,5-dichloro-4-pyridinyl) -1- (7-methoxyspiro [1,3-benzodioxol-2,1'-cyclopentane] -4-yl) ethanone (CAS number 185406-34-2), 2- (3,4-difluorophenoxy) -5-fluoro-N- [cis-4 - [(2-hydroxy-5-methylbenzoyl) amino] cyclohexyl] -) - 3 Piri incarboxamide), (2- (3,4-difluorophenoxy) -5-fluoro-N- [cis-4 - [[2-hydroxy-5- (hydroxymethyl) benzoyl] amino] cyclohexyl] -3-pyridinecarboxamide, CT2820, GPD-1116, ibudilast, 1C 485, KF 31334, KW-4490, lyrimilast ([2- (2,4-dichlorobenzoyl) -6 - [(methylsulfonyl) oxy] -3-benzofuranyl) - urea), N-cyclopropyl -1,4-dihydro-4-oxo-1- [3- (3-pyridinylethynyl) phenyl] -) - 1,8-naphthyridine-3-carboxamide, M- (3,5-dichloro-4-pyridinyl) -4- (difluoromethoxy) -8 - [(methylsulfonyl) amino]) - 1-dibenzofurancarboxamide, ON06126, ORG 20241 (4- (3,4-dimethoxyphenyl) -N-hydroxy -) - 2-thiazolecarboximidamide), PD189659 / PD168787 (Parke-Davis), pentoxifylline (3,7-dihydro-3,7-dimeti l-1- (5-oxohexyl) -) - 1 H-purine-2,6-dione), 5-fluoro-N- [4 - [(2-hydroxy-4-methylbenzoyl) amino] cyclohexyl] - compound 2- (thian-4-yloxy) pyridin-3-carboxamide, picamilast (3- (cyclopentyloxy) -N- (3,5-dichloro-4-pyridinyl) -4-methoxybenzamide), PLX-369 (WO 2006026754), roflumilast (3- (cyclopropylmethoxy) -N- (3,5-dichloro-4-pyridinyl) -4- (difluoromethoxy) benzamide), SCH 351591 (N- (3,5-dichloro-1-oxido-4-pyridinyl) -8-methoxy-2- (trifluoromethyl) -5-quinolinecarboxamide), SelCID (TM) CC-10004 (Calgene), T-440 (Tanabe), tetomilast (6- [2- (3,4-diethoxyphenyl) -4 -thiazolyl] -2-pyridinecarboxylic acid), tofimilast (9-cyclopentyl-7-ethyl-6,9-dihydro-3- (2-thienyl ) -5H-pyrazole [3,4-c] -1,2,4-triazole [4,3-a] pyridine), TPI 1100, UCB 101333-3 (N, 2-dicyclopropyl-6- (hexahydro-1H -azepin-1-yl) -5-methyl-4-pyrimidinamine), V-11294A (Napp), VM554 / VM565 (Vernalis) and zardaverine (6- [4- (difluoromethoxy) -3-methoxyphenyl] -3 (2H ) -pyridazinone);

15) PDE-5 inhibitors: gamma-glutamyl [s- (2-iodobenzyl) cysteinyl] glycine, tadalafil, vardenafil, sildenafil, 4-phenylmethidamino-6-chloro-2- (1-imidazolyl) -quinazoline, 4-phenylmethylamino 6-chloro-2- (3-pyridyl) -quinazoline, 1,3-dimethyl-6- (2-propoxy-5-methanesulfonylamidophenyl) -1,5-dihydropyrazole [3,4-a] pyrimidin-4-one and 1-cyclopentyl-3-ethyl-6- (3-ethoxy-4-pyridyl) pyrazole [3,4-c)] pyrimidin-4-one;

16) PPAR-γ agonists: pioglitazone, pioglitazone hydrochloride, rosiglitazone maleate, rosiglitazone maleate ((-) enantiomer, free base), rosiglitazone maleate / metformin hydrochloride and tezaglitazar;

17) protease inhibitors: alpha-1-antitrypsin proteinase inhibitor, EPI-HNE4, UT-77, ZD-0892, DPC-333, Sch-709156 and doxycycline;

18) statins: atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin;

19) thromboxane antagonists: ramatroban and seratrodast;

20) vasodilators: A-306552, Ambrisentan, Avosentan, BMS-248360, BMS-346567, BMS-465149, BMS-509701, Bosentan, BSF-302146 (Ambrisentan), a peptide associated with the calcitonin gene, daglutrile, potassium dausentan, darusentan , fasudil, iloprost, KS-12615 (daglutril), KS-12792 2AB (daglutril), liposomal treprostinil, PS-433540, sodium sitaxentan, sodium ferulate, TVS-11241 (sitaxentan), TVS-3214 (N- (2-acetyl) -4,6-dimethylphenyl) -3 - [[(4-chloro-3-methyl-5-isoxazolyl) amino] sulfonyl] -2-thiophenecarboxamide), TVS-3711, trapidyl, treprostinyl-diethanolamine and sodium treprostinil;

21) ENAC blockers: amiloride, benzamyl, triamteren, 552-02, PSA14984, PSA25569, PSA23682 and AER002.

A medicament may contain a combination of two or more active ingredients, for example, a combination of two or more specific active ingredients listed in subparagraphs (1) to (21) above. In a preferred embodiment, the medicament contains an active ingredient selected from mometasone, ipratropium bromide, tiotropium and their salts, salmeterol, fluticasone propionate, beclomethasone dipropionate, reproterol, clenbuterol, rrofleponide and their salts, nedocromilum, cromoglisulide, sodium cromoglisolide formoterol, terbutaline, terbutaline sulfate, salbutamol in the form of a base and sulfate, fenoterol, 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) ethylamino] -N- [ 2- [2- (4-methylphenyl) -ethoxy] ethyl] propane sulfonamide, indacaterol, aclidinium bromide, N- [2- (diethylamino) ethyl] -N- (2 - {[2- (4-hydroxy-2-oxo-2,3-dihydro- 1,3-benzothiazol-7-yl) ethyl] amino} ethyl) -3- [2- (1-naphthyl) ethoxy] propanamide or a pharmaceutically acceptable salt thereof (e.g. dihydrobromide); N-cyclohexyl-N ³ - [2- (3-fluorophenyl) ethyl] -N- (2 - {[2- (4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazole-7- yl) -ethyl] amino} ethyl) -β-alaninamide or a pharmaceutically acceptable salt thereof (e.g., di-D-mandelate); salts of [2- (4-chlorobenzyloxy) -ethyl] - [2 - ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethylammonium (for example, heminaphthalene-1,5-disulfonate); salts of (R) -1- [2- (4-fluorophenyl) ethyl] -3 - ((S) -2-phenyl-2-piperidin-1-ylpropionyloxy) -1-azoniabicyclo [2.2.2] octane (for example , bromide or toluenesulfonate); or combinations of any two or more of them.

Specific combinations of active ingredients that may be included in the drug include:

a) formoterol (for example, in the form of a fumarate dihydrate) and budesonide;

b) formoterol (for example, in the form of a fumarate dihydrate) and fluticasone;

c) N- [2- (diethylamino) ethyl] -N- (2 - {[2- (4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl) ethyl] amino} ethyl) -3- [2- (1-naphthyl) ethoxy] propanamide or a pharmaceutically acceptable salt thereof (eg dihydrobromide) and [2- (4-chlorobenzyloxy) ethyl] - [2 - ((R) -cyclohexylhydroxyphenylmethyl) -oxazol-5-ylmethyl] -dimethylammonium (e.g. heminaphthalene-1,5-disulfonate);

d) N- [2- (diethylamino) ethyl] -N- (2 - {[2- (4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl) ethyl] amino} ethyl) -3- [2- (1-naphthyl) ethoxy] propanamide or a pharmaceutically acceptable salt thereof (eg dihydrobromide) and (R) -1- [2- (4-fluorophenyl) ethyl] -3- ( (3) -2-phenyl-2-piperidin-1-ylpropionyloxy) -1-azoniabicyclo [2.2.2] octane (e.g. bromide or toluenesulfonate);

d) N-cyclohexyl-N ³ - [2- (3-fluorophenyl) ethyl] -N- (2 - {[2- (4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazole- 7-yl) ethyl] amino} ethyl) -β-alaninamide or a pharmaceutically acceptable salt thereof (eg, di-D-mandelate) and [2- (4-chlorobenzyloxy) ethyl] - [2 - ((R) -cyclohexylhydroxyphenylmethyl) - oxazol-5-ylmethyl] dimethylammonium (e.g. heminaphthalene-1,5-disulfonate);

e) N-cyclohexyl-N ³ - [2- (3-fluorophenyl) ethyl] -N- (2 - {[2- (4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazole- 7-yl) ethyl] amino} ethyl) -β-alaninamide or a pharmaceutically acceptable salt thereof (eg, di-D-mandelate) and the salt of (R) -1- [2- (4-fluorophenyl) ethyl] -3- ( (S) -2-phenyl-2-piperidin-1-ylpropionyloxy) -1-azoniabicyclo [2.2.2] octane (e.g. bromide or toluenesulfonate).

The term “drug,” as used herein, generally refers to one or more components in a container released in the form of an aerosol when the container is activated in an inhaler. Typically, the drug contains at least one active ingredient and a propellant. In embodiments of the invention, the drug may contain drug components that are introduced into the container before and / or after the drug propellant is introduced into the container, thereby producing a drug consisting of drug components and a drug propellant.

The following describes the preferred embodiments of the present invention, given solely as examples, with reference to the accompanying graphic materials described below.

Figure 1 shows a schematic illustration of a filling system that can be used according to a preferred embodiment of the present invention for introducing into a container a suspension or solution of a pharmaceutical substance in a pressure propellant.

Figure 2 schematically shows a pMDI with manual control, including a container made according to a preferred embodiment of the present invention.

Figure 3 schematically shows a pMDI with automatic control, which is driven by a breath-activated mechanism, comprising a container made in accordance with a preferred embodiment of the present invention.

Figure 4 presents the data on the released mass obtained for aerosols sprayed from containers that have been purged after holding the metering valve open for various periods of time.

Figure 5 presents the data on the released mass obtained for aerosols sprayed from the container, not past purge, after holding the metering valve open for various periods of time.

Fig.6 shows the data from Fig.4 and 5 in a single coordinate system for ease of comparison.

Figure 7 presents dose weight data (expressed as a percentage of the dose indicated on the label of a given drug) obtained for a drug sprayed from both purged containers and non-purged containers after holding the metering valve open for various periods of time.

Various preferred embodiments of the present invention are described below with reference to drawings, where appropriate. The same numerical designations are used to designate the same components of the preferred embodiments.

Figure 1 shows a known filling system having a filling head 2 for filling a container 138 with a measured volume of a suspension or solution of a pharmaceutical substance in a propellant under pressure.

The filling head 2 is included in the circulation line, indicated by the general position 170, in which a propellant containing a pharmaceutical substance is circulated under pressure in the form of a suspension or solution. The circulation line 170 includes a mixing tank 172 that maintains the propellant containing the pharmaceutical substance in the form of a suspension or solution.

The mixing tank 172 is under pressure, like the rest of the circulating line 170, so that the propellant is not only under pressure, but also stored in the form of a liquid, where the boiling point of this propellant is below ambient temperature. Line 176 connects the outlet channel from mixing tank 172 to a pump 178 for pumping propellant throughout the circulating line 170. Another line 180 connects the pump 178 to the inlet side of the inlet valve 182. Another line 183 connects the outlet side of the inlet valve 182 with a metering chamber 184. Dosing chamber 184 is configured to load a measured volume of the propellant containing the pharmaceutical substance, in the form of a suspension or solution, when the inlet valve 182 is opened. The indicated measured volume corresponds to a volume to be entered into the container 138 through the filling head 2. Another line 186 connects the metering chamber 184 from the filling head 2.

Although in the embodiment of FIG. 1 a one-stage method of filling under pressure is shown, a two-stage method can be used instead, for example, in which only the propellant under pressure is circulated in these lines and the remaining components of the drug are preliminarily introduced into container 138, and then sealing said container 138 with a valve and filling by filling head 2. In the case of a two-step process, mixing tank 172 may be absent Th.

Thus, FIG. 1 shows a conventional pressure filling method. However, according to the present invention, no air is removed from the container 138 at any stage before being filled by the filling head 2. Thus, the container 138 is essentially filled with air when the container 138 is sealed using the metering valve 134 (and this the container may further comprise one or more components of the drug, such as a pharmaceutical component (API), a co-solvent, a surfactant, and so on, if the filling method is two hstadii), and indeed, when the container 138 reaches the filling head 2, and immediately before filling. After dispensing a metered amount of propellant (including the pharmaceutical component in a one-step process) to container 138 by means of filling head 2, the filled container contains the drug in a suitable dosage form, as well as air. Typically, the contents of the container in accordance with the present invention will thus be at a higher pressure than the contents of the container during the normal purge step before sealing the container with a metering valve and will contain significantly more air. Not wishing to be bound by theory, it is argued that such a higher pressure can lead to a better filling of the metering valve and, therefore, provides an improved and more stable released spray mass even after holding the valve in the open position for a long period of time.

Such a container obtained by the method of FIG. 1 can be used in any suitable pressurized metered dose inhaler (pMDI). Figure 2 schematically shows a manually controlled inhaler 1 comprising a container 138 containing a medicament for administering doses upon actuation. The inhaler includes a drive mechanism housing 3 and a mouthpiece 13 through which the user inhales the nebulized drug. The valve is located in the release unit at the base of the housing 3 of the drive mechanism.

The user actuates the pMDI 1 of FIG. 2 to dispense a dose into the mouthpiece 13 for inhalation by pressing the actuator 15 from top to bottom with the finger, lowering the container 138, thereby opening the valve 134 and dispensing the dose from the release unit to the mouthpiece 13 by high pressure of the drug in the container.

The container obtained by the method according to FIG. 1 can also be used in a pressure-controlled metered dose inhaler (pMDI). Figure 3 schematically shows an inhalation activated inhaler 1 comprising a container 138 containing a drug for administering doses by automatically actuating in response to starting the device by inhalation.

Briefly, the inhaler 1 comprises a housing 10 including a mechanism triggered by inhalation (4, 6, 50-53, 55, 57, 58, 130, 150, 160, 200, 210, 250). This mechanism includes, inter alia, a breath-opening damper 57, which rotates about a rotation axis 58 when the user inhales through the mouthpiece. This ensures the separation of some contacts (53, 55, 150, 200, 250) and the rotation of the connecting element 50 relative to its pivot point 51. As a result of this, the energy of the spring 6 is held, which is held until it is released in the compressed position. Spring 6 biases clutch 4 downward, exerting pressure on container 138 from top to bottom. This presses the metering valve 134 against the release unit 62, thereby releasing a dose of the drug 60, as shown in the image.

A more detailed description of the mechanics and components of the shown mechanism BA1 can be found in WO 2008/082359.

EXAMPLES

To illustrate the advantages of various aspects of the present invention, both the purged and non-purged containers were tested and the results compared. To understand the method used, it should be borne in mind that the phenomenon under study is a partial re-filling of the metering valve chamber, and not its partial emptying. Therefore, it is an actuation following a previous actuation, in which the inhaler is held in the actuation position for a period of time that is involved and which is to be evaluated.

Example 1

Three containers for three inhalers were collected and filled with the drug in the usual way, that is, with a purge step, in which the container was purged with a propellant, and then the container was sealed with a metering valve, followed by filling with the drug. Each inhaler was tested as follows:

1) was actuated in the usual way to spray aerosol;

2) they were actuated again and held in this actuated position (i.e., kept the metering valve open) for a first predetermined period of time (indicated in column 1 of Table 1);

3) weighed;

4) they were actuated again and held in this actuated position (i.e., kept the metering valve open) for the first predetermined period of time (indicated in column 1 of Table 1);

5) weighed;

6) powered in the usual way;

7) weighed.

The released mass after the retention time was calculated as the mass of the inhaler in step (5) minus the mass of the inhaler in step (3) and the mass of the inhaler in step (7) minus the mass of the inhaler in step (5). The average value of the results obtained with two actuations after each retention time was calculated. Finally, the total average of the three inhalers was calculated and recorded (in column 2 of Table 1). For each inhaler, the process was repeated with the following predetermined period of time and so on, with the results shown in Table 1.

Table 1 Valve holding time (seconds) The average released mass (mg) after retention time 2 76.1 5 76.0 10 76,2 twenty 68.5 thirty 47.5 fifty 22.1 90 11.1

As clearly follows from the graphical representation (Figure 4) of the results shown in Table 1, the released mass of the sprayed aerosol after holding the valve in the open position for a certain period of time is significantly reduced with longer periods of time. This is undesirable since the released aerosol mass directly affects the delivered dose of the active pharmaceutical ingredient of the drug and, therefore, if the inhaler metering valve is kept open for too long, the patient potentially receives a lower dose of the drug.

Example 2

For comparison with Example 1, an inhaler container was collected and filled with a propellant according to aspects of the present invention. The container was prepared and filled in exactly the same way as in Example 1, except that there was no purge step, that is, the container in the inhaler in Example 2 did not pass purge. As in Example 1, in Example 2, the inhaler was examined as follows:

1) was actuated in the usual way to spray aerosol;

2) they were actuated again and held in this actuated position (i.e., kept the metering valve open) for a first predetermined period of time (indicated in column 1 of Table 1);

3) weighed;

4) they were actuated again and held in this actuated position (i.e., kept the metering valve open) for the first predetermined period of time (indicated in column 1 of Table 1);

5) weighed;

6) powered in the usual way;

7) weighed.

The released mass after the retention time was calculated as the mass of the inhaler in step (5) minus the mass of the inhaler in step (3) and the mass of the inhaler in step (7) minus the mass of the inhaler in step (5). The average value of the results obtained with two actuations after each retention time was calculated. The average value of the results obtained with two actuations after each retention time was calculated and recorded (in column 2 of Table 1). The process was repeated with the following predetermined time period, and so on, to obtain the results shown in Table 2. The time periods in Example 2 include longer periods of time than in Example 1, but the results are completely comparable.

table 2 Valve holding time (seconds) The average released mass (mg) after retention time 2 77.0 thirty 72.6 60 67.6 120 54.3

As clearly follows from the graphical representation (Figure 5) of the results shown in Table 2, the released mass of the spray aerosol after holding the valve in the open position for a period of time for the inhaler of Example 2 does not show such a significant reduction for longer periods of time compared to the inhalers of Example 1. Thus, the inhaler of Example 2 functions much better than the inhalers of Example 1 in relation to a more stable released mass of aerosols sprayed. This is clearly seen from Figure 6, which shows data obtained using a container that did not purge (Table 2), in comparison with data obtained using containers that have passed purge (Table 1).

Example 3

As described above, the released aerosol mass has a direct effect on the delivered dose of the active pharmaceutical ingredient of the drug and, therefore, on the potential dose of the drug received by the patient when the inhaler is activated. To confirm this, ninety purged containers and thirty non-purged containers (for comparison) were prepared in the same manner as described above. Each container contained the same predetermined and known number of doses of the selected drug, which made it possible to determine the beginning, middle and end of the service life of the containers.

Sixty purged containers were selected for the study. Each container at the beginning of its life was placed in an inhaler and actuated in the usual way for the initial opening of the metering valve. In the second and third actuation, the metering valve was kept open for a predetermined time period of 15, 30 or 45 seconds (twenty containers for each time period) and then the inhaler was actuated in the usual manner for the fourth time. The delivered dose was measured together for the third and fourth actuations using a standard device for collecting doses delivered by the inhaler at a flow rate of 80 liters per minute. Data was recorded, after which each container was actuated a sufficient number of times to reach the middle of the life of each inhaler (i.e., approximately half the doses were released). The measurement process was then repeated, that is, each container was actuated once in the usual way and twice while keeping the metering valve open for a predetermined period of time of 15, 30 or 45 seconds. The inhaler container was then actuated again and the delivered dose was measured together for the third and fourth actuations. Data was recorded, after which each container was actuated a sufficient number of times to reach the end of the life of each inhaler (that is, almost all remaining doses were released). The measurement process was then repeated, that is, each container was actuated once in the usual way and twice while keeping the metering valve open for a predetermined period of time of 15, 30 or 45 seconds. The inhaler container was then actuated again and the delivered dose was measured together for the third and fourth actuations. Then, the data obtained at the end of the service life, the middle of the service life and the beginning of the service life were combined, and the average values of these sixty measurements were calculated as a percentage of the dose indicated on the label of this drug, and these average values are shown in column 2 of Table 3. To obtain data on the dose delivered after preliminary holding the metering valve in the open position for 10 seconds, instead of twenty examined thirty containers that did not pass purge (also at the beginning, middle and end of the term service, thus making a total of ninety measurements). The average values of these data are also shown in column 2 of Table 3.

For comparison, such testing was carried out using thirty purged containers containing the same amount of the same drug. Testing of containers that were purged was also carried out in the same way as testing of containers that did not pass purge, in particular, they were also performed at the beginning, middle, and end of the service life of the containers. The data shown in column 3 of Table 3 is an average of thirty values (three from each of ten containers) at each retention time. When using purged containers, the valves were kept open for 10, 30, or 50 seconds before measuring the mass of the dose delivered during subsequent actuation. Nevertheless, the data presented are completely comparable.

Table 3 Valve holding time (seconds) Delivered dose (% of declared on the label) after retention time Non Purge Containers Purge Containers 10 95.6 89.4 fifteen 93.0 - thirty 89.2 70.9 45 83,4 - fifty - 35.5

As can be seen from Fig. 7, where the data of Table 3 are graphically presented, the decrease in the mass of the dose released from the inhaler after keeping the valve open during the previous actuation is significantly less if the container did not pass purging before filling with the drug. This is an advantage because the patient is less likely to receive a lower dose of medication from an inhaler containing a non-purged container than an inhaler containing a purged container, even if the patient accidentally holds or leaves the inhaler container in an activated state, i.e. with open metering valve.

Claims (18)

1. A method of obtaining a filled container for an inhaler, comprising the steps of:
providing a container with a housing configured to contain the drug and with an opening for loading the drug, said container being substantially filled with air under ambient conditions;
sealing said opening of an air-filled container;
attaching said sealed air-filled container to a filling device; and
distributing pressurized liquids and / or gas from said filling device to said pressurized air-filled container, said pressurized liquid and / or gas containing at least a propellant,
wherein:
prior to said step of dispensing pressurized liquids and / or gas, the sealed container is substantially free of propellant; and
after this stage of the distribution of pressurized liquid and / or gas, the sealed container is essentially filled with at least a first part of the propellant and a second part of air. 2. The method according to p. 1, in which additionally:
before said sealing step of said opening of the air-filled container, said air-filled container is connected to the drug dispenser; and
dispensing a metered amount of a drug from said drug dispensing device to said container filled with air,
at the same time, at the stage of sealing the openings of the container filled with air, the specified opening of the container containing the drug and air is sealed with a metering valve. 3. The method of claim 1, wherein said pressurized liquid and / or gas dispensed from the filling device into a sealed air-filled container further comprises a medicament. 4. The method according to p. 2 or 3, in which the drug contains an active ingredient selected from mometasone, ipratropium bromide, tiotropium and their salts, salmeterol, fluticasone propionate, beclomethasone dipropionate, reproterol, clenbuterol, rofleponide and salts, nedocromil sodium , flunisolide, budesonide, formoterol fumarate dihydrate, terbutaline, terbutaline sulfate, salbutamol in the form of a base and sulfate, fenoterol, 3- [2- (4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl) hydrochloride ethylamino] -N- [2- [2- (4-methylphenyl) ethoxy] ethyl] -p ropansulfonamide, indacaterol, aclidinium bromide, N- [2- (diethylamino) ethyl] -N- (2 - {[2- (4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazole-7- il) ethyl] amino} ethyl) -3- [2- (1-naphthyl) ethoxy] propanamide or a pharmaceutically acceptable salt thereof (e.g. dihydrobromide); N-cyclohexyl-N ³ - [2- (3-fluorophenyl) ethyl] -N- (2 - {[2- (4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazole-7- il) ethyl] amino} ethyl) -β-alaninamide or a pharmaceutically acceptable salt thereof (e.g., di-D-mandelate); salts of [2- (4-chlorobenzyloxy) ethyl] - [2 - ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethylammonium (for example, heminaphthalene-1,5-disulfonate); salts of (R) -1- [2- (4-fluoro-phenyl) -ethyl] -3 - ((S) -2-phenyl-2-piperidin-1-yl-propionyloxy) -1-azonia-bicyclo [2.2 .2] octane (eg bromide or toluenesulfonate); or combinations of any two or more of them. 5. The method according to p. 2 or 3, in which the drug contains at least one excipient. 6. The method of claim 5, wherein the excipient comprises at least one of: a surfactant, a co-solvent, and a lubricant. 7. The method according to any one of paragraphs. 1-3, in which the propellant contains HFA 227 or HFA 134a. 8. The method according to p. 2, in which the average released mass from the filled container is 72.6 mg after a holding time of the metering valve open equal to 30 seconds. 9. The method of claim 8, wherein the average released mass from the filled container is 67.6 mg after a holding time of the metering valve open of 60 seconds. 10. The method according to p. 2, in which the delivered dose in a filled container is 95.6% of the claimed after holding the metering valve open, equal to 10 seconds. 11. The method according to p. 10, in which the delivered dose in a filled container is 83.4% of the claimed after holding the metering valve open, equal to 45 seconds. 12. The filled container for the inhaler obtained by the method according to any one of paragraphs. 1-11. 13. A filled container according to claim 12, essentially filled with at least a first part of the propellant, a second part of air, and a third part of a medicine, preferably containing at least one excipient. 14. The filled container of claim 13, wherein the excipient comprises at least one of: a surfactant, a co-solvent, and a lubricant. 15. A filled container according to any one of paragraphs. 12-14 having a coating, preferably at least on the inner surface of the container. 16. The filled container of claim 15, having a coating of a fluorine-containing polymer, preferably perfluoroalkoxyethylene (PFA), polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), polyethylene terephthalate (PET) or the like. 17. A filled container according to claim 15, the coating of which is applied by spraying or plasma spraying. 18. A metered dose inhaler, preferably a breath activated inhaler, comprising a filled container according to any one of claims. 12, 13 or 14.

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